ABSTRACT The accumulation of somatic DNA mutations over time is a hallmark of aging in many tissues. However, the causal role of somatic mutations in age-associated disorders other than cancer is a matter of debate and remains largely unexplored in the setting of cardiovascular disease. Recent large exome sequencing studies in humans have shown that aging is inevitably associated with an increased frequency of somatic mutations in the hematopoietic system, which provide a competitive growth advantage to the mutant cell and thus allow its clonal expansion (somatic mutation-driven clonal hematopoiesis). Supporting this notion, our recent study in Science (Fuster et al, Science 2017) demonstrated that the clonal expansion of hematopoietic cells deficient in TET2, one of the most frequently mutated genes in blood cells of elderly individuals, accelerates atherosclerotic plaque formation (atherogenesis) in hyperlipidemic mice. While this study provided experimental evidence of causality and mechanistic insight supporting that somatic mutations in blood cells are a new contributor to atherosclerotic cardiovascular disease, there are limitations in extrapolating these results to the clinical scenario. Specifically, in our experimental study, clonal hematopoiesis preceded atherosclerotic plaque induction; however, clinical studies show that substantial subclinical atherosclerosis is already present in most individuals at ages that typically precede the development of somatic mutation driven-clonal hematopoiesis. Furthermore, an increasing percentage of individuals are prophylactically treated with cholesterol-lowering drugs, but the impact of clonal hematopoiesis in plaque arrest/regression induced by blood cholesterol lowering remains completely unexplored. Based on these clinical facts, the overarching objective of this proposal is to investigate whether somatic TET2 mutation-driven clonal hematopoiesis affects atherosclerosis in the clinically relevant settings of atherosclerotic plaque progression or arrest/regression. Aim 1 will evaluate the effects of the clonal expansion of TET2-deficient hematopoietic cells in atherosclerotic plaque progression in hyperlipidemic mice and in plaque arrest/regression induced by blood cholesterol lowering. Aim 2 will dissect the molecular mechanisms underlying the effects of TET2 mutations in plaque remodeling. Aim 3 will explore the hypothesis that interventions targeting mechanistic nodal points downstream of TET2 deficiency in the hematopoietic system protect against accelerated atherosclerosis in mice exhibiting TET2 loss of function-driven clonal hematopoiesis.